Increases in Protease CSF concentrations with Ketoconazole (P-gp inhibitor)
Khaliq et al. Clin Pharmacol Ther 2000 Dec;68(6):637-46.
Notes:
In this pharmacokinetic study, 12 HIV-positive patients receiving 400 mg of ritonavir and 400 mg of saquinavir BID were given ketoconazole 200-400 mg daily for 10 days. Blood samples were collected over the daytime 12-hour dosing interval of the protease inhibitors at baseline and after 10 days of ketoconazole coadministration. One set of paired CSF and blood samples was collected between 4 and 5 hours after the dose on both days.
RESULTS: Ketoconazole significantly increased area under the plasma concentration-time curve, plasma concentration at 12 hours after the dose, and half-life of ritonavir by 29% (95% confidence interval (CI), 13%-46%), 62% (95% CI, 37%-92%), and 31% (95% CI, 13%-51%), respectively. Similar increases of 37% (95% CI, 4%-81%), 94% (95% CI, 41%-167%), and 38% (95% CI, 15%-66%), respectively, were observed for these parameters for saquinavir. Ketoconazole significantly elevated ritonavir CSF concentration by 178% (95% CI, 59%-385%), from 2.4 to 6.6 ng/mL, with no change in paired unbound plasma level (26 ng/mL); this led to a commensurate 181% increase (95% CI, 47%-437%) in CSF/plasma unbound ratio. All pharmacokinetic changes were unrelated to ketoconazole dose or plasma exposures. Corresponding changes for saquinavir CSF pharmacokinetics were insignificant (P > .06); saquinavir CSF levels were unmeasurable in 7 patients (ɘ.2 ng/mL).
The authors concluded that the disproportionate increase in CSF compared with plasma concentrations of ritonavir is consistent with ketoconazole inhibiting both drug efflux from CSF and systemic clearance. Clinical implications of these data are still unclear.
Khaliq Y, Gallicano K, Venance S, Kravcik S, Cameron DW. Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus. Clin Pharmacol Ther 2000;68:637-46.